making progress toward universal influenza vaccines · faster response capability recombinant-based...

United States Department of

Health & Human Services Office of the Assistant Secretary for Preparedness and Response

Rick Bright, PhD Director, Influenza Division

Biomedical Advanced Research and Development Authority (BARDA) Office of the Assistant Secretary for Preparedness & Response

8th WHO International Partners Meeting Sao Paulo, Brazil, March 17-18, 2015

Making Progress Toward Universal

Influenza Vaccines

ASPR: Resilient People. Healthy Communities. A Nation Prepared.

Public Health Impact of Influenza

1918 ‘Spanish’ Pandemic

20%-40% infected

worldwide

675,000 deaths in US

50M deaths worldwide

2009-2010 H1N1

Pandemic

74 countries affected

60.8M infected

in US

12,469 deaths in US

274,304 hospitalizations

in US

123,000-203,000 deaths

worldwide

Seasonal Influenza Epidemic

in US

$87.1B economic

burden every year

$10.4B medical

costs every year

3,000-49,000 deaths

every year

>200,000 hospitalizations

every year

5%-20% infected

every year

1

Presenter

Presentation Notes

1918 ‘Spanish’ Pandemic: 20% - 40% infected worldwide http://www.flu.gov/pandemic/history/ 50M deaths worldwide http://www.flu.gov/pandemic/history/ 675,000 deaths in the US http://www.flu.gov/pandemic/history/ 2009-2010 H1N1 Pandemic: 74 countries were affected by the H1N1 pandemic http://www.flu.gov/pandemic/history/ 123,000 -203,000 deaths were estimated worldwide Simonsen et al., PLoS Med. 2013 Nov;10(11):e1001558. doi: 10.1371/journal.pmed.1001558. Epub 2013 Nov 26. 60.8M (range: 43.3–89.3 million) infected in the US Shrestha SS, et al., Clin Infect Dis. 2011 Jan 1;52 Suppl 1:S75-82. 274,304 (195,086–402,719) hospitalizations in the US Shrestha SS, et al., Clin Infect Dis. 2011 Jan 1;52 Suppl 1:S75-82. 12,469 deaths (8,868–18,306) in the US Shrestha SS, et al., Clin Infect Dis. 2011 Jan 1;52 Suppl 1:S75-82. Seasonal Influenza in the US: 5% - 20% Americans infected with influenza in the US every year �http://www.cdc.gov/flu/about/qa/disease.htm >200,000 hospitalizations from seasonal flu-related complications in the US every year�http://www.cdc.gov/flu/about/qa/disease.htm 3000 - 49,000 deaths from seasonal influenza in the US every year http://www.cdc.gov/flu/about/qa/disease.htm $10.4B of medical costs from seasonal influenza in the US every year�Molinari, Ortega-Sanchez, Messonnier, Thompson, Wortley, Weintraub, Bridges The annual impact of seasonal inﬂuenza in the US: Measuring disease burden and costs doi:10.1016/j.vaccine.2007.03.046 PMID 17544181 (estimated from 2003 US population) $87.1B of economic burden from seasonal influenza in the US every year�Molinari, Ortega-Sanchez, Messonnier, Thompson, Wortley, Weintraub, Bridges The annual impact of seasonal inﬂuenza in the US: Measuring disease burden and costs doi:10.1016/j.vaccine.2007.03.046 PMID 17544181 (estimated from 2003 US population)


Influenza Viruses Constantly Evolve

2

H1N1, H1N1v H2N2, H1N2v H3N2, H3N2v H5N1, H5N6 H9N2, H7N7 H7N9, H10N8 H6N1, H7N2 H7N3, H10N7


Pandemic Influenza Response Capabilities Prior 2005

3

• No National Strategy for influenza pandemic preparedness • No pre-pandemic vaccine or antiviral stockpile – federal or

state • Limited domestic manufacturing capability for pandemic

response • Lack of global vaccine supply for a pandemic response • Candidate pandemic influenza vaccines were poorly

immunogenic • All US licensed seasonal vaccines were egg-based (1940s-

1950s technology) • No cell-based and no recombinant-based influenza

vaccine licensed • No adjuvanted influenza vaccines licensed in U.S.


Therapeutics

Respiratory Devices/Masks

International Vaccine Capacity

Building

Vaccine & Adjuvant Stockpile

Vaccines

Diagnostics

BARDA Pandemic Influenza Strategy

BARDA Influenza Division

Enable 500M doses of pandemic vaccine production capacity in developing countries

Stockpile vaccines against influenza strains with pandemic potential

Provide pandemic vaccine for U.S. within 6 months (or less) of a pandemic declaration (600M doses)

Reducing the Impact of Influenza Virus Infection

Develop rapid POC/ pre-symptomatic diagnostics

Develop low cost, easy to use respirators suitable for all ages with universal components

4

Advanced development of antiviral drugs & therapeutics

Develop reusable masks and respirators to address surge need during a pandemic

Develop influenza vaccines that induce broader, longer duration of immunity

More, Faster, & Better!


More Vaccines

sanofi pasteur – Swiftwater, PA

Egg-based Vaccines

2013 ISPE Facility of the Year

1st US FDA approved pandemic-ready site for cell-based vaccines & adjuvant

Centers for Innovation in Advanced Development and Manufacturing (CIADM)

5

Presenter

Presentation Notes

MORE: egg supply, facilities, CIADM, and adjuvants.

ASPR: Resilient People. Healthy Communities. A Nation Prepared. 6

Changing Seasonal Vaccine Portfolio


Licensed/Active Influenza Vaccine Producers

BARDA/WHO Cooperative Agreement Grantees

More International Vaccine Manufacturing Capacity

Mexico Birmex

Brazil Instituto Butantan South

Africa Biovac

India Serum

Institute

Vietnam IVAC

VABIOTECH PATH

Thailand GPO Indonesia

Bio Farma

Egypt VASERA

South Korea Green Cross Serbia

Torlak Institute

BARDA/WHO Licensed Vaccine for Human Use (as of 2/2014)

Kazakhstan RIBSP

Romania Cantacuzino

Institute

7


Faster Response Capability

Recombinant-based Influenza Vaccine Flublok®

Protein Sciences Licensed 01/16/2013

Influenza Vaccine Manufacturing Improvement Initiative

Fill Finish Manufacturing Network

Centers for Innovation in Advanced Development and Manufacturing

(CIADM)

8

Presenter

Presentation Notes

FASTER: Recombinants, IVMI, CIADM, & FFMN


• Vulnerable to antigenic drift and shift • Antibodies target highly variable regions of HA and NA • Single site mutations can impact immunogenicity

• Provide minimal cross-protection within subtypes or against other subtypes of influenza

• Short duration of immunity • Requires viral isolate for production • Predominantly produced in chicken eggs

Limitations of Current Influenza

Vaccines

9


Egg-based inactivated

Cell-culture inactivated

LAIV

Recombinant (SUV & VLPs)

Universal

Vectors/ Adjuvant

WIV Egg inactivated

Split

Split w/ iscomatrix

QIV Split

H5N1 AS03

WIV

H5N1 WIV w/ Adjuvant

Split

Adimmune- Taiwan

Split w/ SPA03 H5N1, WIV

WIV

QIV, High dose, intradermal

EB66; H5N1 Monkey Kidney Cell MDCK subunit (EU) US

2009/2010 Vero, Influject/ Cevapan(EU)

dNS1 - Vero Egg H5N1/H9N2/H7N9 Egg, H5N2

H5 Egg, Thailand

Serum Institute of India Ltd

Egg QIV, Egg Egg (Russia)

dNS1- Vero

VLP / HA VLP, Insect cells VLP, 293 cells rHA, Plants rHA Insect cells VLP, Plants rHA, Insect cells VLP, Insect Cells

Salmonella, Oral Yeast, IN - Oral

Salmonella, Oral Chimeric VLP + microneedles

Molecular HAs

NYU / MSSM HA stalk; Chimeric

Novel peptides

NP & ISS Tech Peptide based

HA, Flagellin, e coli

MVA Based Adenovirus M & NP Adenovirus Adenovirus, Oral

Split

MVA

MVA Based

DNA DNA / Vaxfectin

Influenza Vaccine Landscape

20MAR2014

M2e Liposome

rHA, Plants

rHA, Plants

DNA / SnyCon w/ Electroporation

rHA Insect Cells

Mass Gen Hospital Listeria

Pre Clinical Phase 1 Phase 2 Phase 3 Market Approval

HuaLan

Pandemic

Seasonal

H1N1 Cell; HN-VAC (India)

Seasonal

Seasonal Seasonal

Institutul Cantacuzino

Split

Egg, Thailand

Egg, Thailand

PER.C 6

H1 Egg, Thailand

Egg inactivated SynBio LAIV

Proprietary Adjuvant

Seasonal

COBRA HA VLP

Vero, Influject/ Cevapan(EU)

Japan EB66

NIAID Nanoparticle

Pandemic

Seasonal

Pandemic

Seasonal & Pandemic

US License

EB66

rHA + GLA-SE

Mar 2014 Study Start


Cell-based Vaccines

Egg-based Vaccines

Recombinant Vaccines

Universal Vaccines

Flublok® Licensed 01/16/13

FLUCELVAX® Licensed 11/20/12

H5N1 Vaccine Licensed 04/17/07

Advanced Development Begins FY15

BARDA is Achieving National Pandemic Influenza Vaccine Goals

More, Faster, & Better Vaccines! 11

Presenter

Presentation Notes


A vaccine that provides safe, effective and long-lasting immunity against a broad spectrum of antigenically divergent influenza viruses in all ages and people in high risk groups

Universal Influenza Vaccine

Adapted from: Paul Lewis, MD Oregon State Public Health


Transformative Approach: Bringing it all together

Universal Influenza Vaccine

• Exploit existing vaccines

13

Presenter

Presentation Notes

BETTER: adjuvanted vaccines (QPAN and Novartis and now SP) and Universal Vaccine


Toward a Universal Influenza Vaccine: Current Landscape

No Phase 3 or Market Approved Universal Influenza Vaccines 14


• New science ─ New/alternate regulatory pathways ─ New markers of immunity ─ Alternate production/analytical methods ─ New antigen/adjuvant combinations ─ Large scale or adaptive clinical programs

• New partnerships ─ Public/private partnerships ─ New consortiums/collaborations/Mergers & Acquisitions

• Funding ─ Up to $1B per candidate from preclinical to licensure

Developmental Challenges for Universal Vaccines

15


Broad Agency Announcement (BAA)

16

BAA-13-100-SOL-00019 supports development of MCMs for pandemic influenza. 5.1 Advanced development of novel influenza vaccine candidates which have achieved TRL 6 or greater. Support for advanced development of novel influenza vaccine candidates with the potential to stimulate a broader and more effective immune response than currently available products. Data should be provided that demonstrates statistically-relevant improvements in immunogenicity/efficacy as compared to existing vaccines. Proposed activities should enable improvements to key vaccine attributes, including dose schedule, time to onset of protection, induction of improved immunogenicity, broader cross-protection across influenza A virus subtypes, and duration of protection. Use of approved or novel adjuvants to achieve enhanced or broadened immunogenicity may also be a component of the advanced development program.


Universal Influenza Vaccines: Draft Request for Proposal (RFP)

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https://www.fbo.gov/index?s=opportunity&mode=form&id=0e8a2a57a94d08a6989e292485f8c65b&tab=core&_cview=0

https://www.fbo.gov/index?s=opportunity&mode=form&id=0e8a2a57a94d08a6989e292485f8c65b&tab=core&_cview=0


Target Product Profile for

More Effective Influenza Vaccines Transformative

Property/Vaccine Desired Primary Characteristics

Breadth of Protection

Protects against antigenically divergent influenza A viruses and viruses from both influenza B virus lineages

Efficacy Shows 20% or greater efficacy above a licensed influenza vaccine comparator as measured by clinical endpoints or surrogate endpoints (e.g. seroprotection or seroconversion rates)

Duration of Immunity

Protects for two years or more against influenza A subtypes and influenza B lineages

Priming Immunity

Primes for baseline immunity such that a single dose of pandemic influenza vaccine will boost immune response to protective levels against the pandemic influenza virus

Safety Comparable to licensed vaccines

18


Influenza: An Integrated Response

Vaccines

Therapeutics Diagnostics

Early Detection Early Response Saving Lives

19


Website: https://www.medicalcountermeasures.gov/

• Information on the open influenza BAAs and RFPs • Information on setting up a TechWatch meeting with BARDA to discuss your technology

https://www.medicalcountermeasures.gov/



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